Double-Intensive Therapy in High-Risk Multiple Myeloma
`By J.L, Harousseau, N. Milpied, J.P, Laporte, P. Collombat, T. Facon, J.D. Tigaud, P. Casassus, F. Guilhot,
`N. Ifrah, and C. Gandhour
`A high remission rate is achieved with high-dose melphalan
`(HDM) in multiple myeloma (MM), and autologous transplan­
`tation of hematopoietic stem cells allows a prompt hehiato-
`logic recovery after high-dose therapy. We treated 97 pa­
`tients with high-risk MM (group 1; 44 advanced MM including
`14 primary resistances and 30 relapses; group 2; 53 newly
`diagnosed MM) with a first course of HDM. For responding
`patients a second course of high-dose therapy with hemato­
`poietic stem ceil support was proposed. After the first HDM,
`the overall response and complete remission rates were 71 %
`and 25% with no significant difference between the two
`groups. The median durations of neutropenia and thrombocy­
`topenia were significantly longer in group 1 (29.5 days and 32
`days, respectively) than in group 2 (23 days and 17 days,
`respectively). This severe myelosuppression led to eight
`toxic deaths and to the fact that only 38 of the 69 responders
`could proceed to the second course (three allogenic and 35
`autologous transplantations). Among the 35 patients under­
`
`going autologous transplantation (10 in group 1, 25 in group
`2), 31 received their marrow unpurged collected after the first
`HDM, and four received peripheraT blood stem cells. The
`median durations of neutropenia and thrombocytopenia
`after autologous transplantation were 24 days and 49 days,
`respectively. Two toxic deaths and nine prolonged thrombo­
`cytopenias were observed. The median survival for the 97
`patients was 24 months (17 months in group 1, 37 months in
`group 2) and the median duration of response was 20
`months. The only parameters that have a significant impact
`on the survival are the age (±50 years) and the response to
`HDM. The median survival of the 35 patients undergoing
`autologous transplantation is 41 moriths, but the median
`duration of remission is 28 months with no plateau of the
`remission duration curve. Patients responding to HDM may
`have prolonged survival, but even a second course of high-
`dose therapy probably cannot eradicate the malignant clone.
`© 7992 by The American Society of Hematology.
`
`IN THE LAST few years, high-dose therapy has been
`introduced in the management of multiple myeloma
`(MM). In 1983, McElwain and Powles' treated nine pa­
`tients with high-dose melphalan (HDM) and obtained
`three complete remissions (CR). This preliminary experi­
`ence was amplified, and Selby et aE published updated
`results on 58 patients. The conclusion of this study was that
`a high CR rate could be achieved with HDM, but it would
`be at the expense of a severe myelosuppression with a high
`toxic death rate. However, the median duration of remis­
`sion was only 19 months.
`Autologous bone marrow transplantation (ABMT) is
`another approach of high-dose therapy. Barlogie et aP have
`shown that the duration of neutropenia was shorter and the
`incidence of serious infections lower in patients receiving
`an autologous bone marrow support. The same investiga­
`tors have also shown that ABMT allows a prompt hemato­
`poietic recovery after a myeloablative treatment, such as
`the combination of HDM and total body irradiation (TBI).'*
`We tried to combine these two modalities of high-dose
`therapy in young patients with poor prognosis MM. The
`objectives of the first course of HDM, performed without
`any hematopoietic support, were to achieve a high tumor
`cell mass reduction and an in vivo purging of the marrow
`before the second course. The second course was followed
`by the reinfusion of hematopoietic stem cells collected
`during chemoinduced remission. The objective of this
`second course was to maintain the remission obtained by
`the first course.
`The preliminaiy report on two patients was encourag­
`ing,* and we present here the updated data concerning 97
`patients.
`
`MATERIALS AND METHODS
`
`Patients
`From April 1984 to July 1990, 97 patients less than 70 years old
`and treated in nine French centers received at least one course of
`HDM for poor-prognosis MM. Two groups of patients were
`analyzed.
`
`Blood, Vol 79, No 11 (June 1), 1992: pp 2827-2833
`
`Group I: Advanced MM. This group consisted of 44 patients
`either primarily refractory to at least two protocols of conventional
`chemotherapy, including the VAD regimen* (14 patients), or in
`relapse (30 patients). Relapses were further divided into the
`following: sensitive to standard-dose chemotherapy (5 patients),
`untested (14 patients), or resistant (11 patients).
`Group 2: Newly diagnosed MM. In this group of 53 patients
`HDM was administered as part of frontline therapy, either after
`one to three cycles of debulking chemotherapy or to patients
`responding to their first conventional treatment regimen. Only two
`patients did not receive debulking treatment before HDM.
`The initial characteristics of the patients are shown in Table 1.
`The study tyas approved by the Institutional Review Board.
`Informed consent was obtained in each case according to the
`Declaration of Helsinki.
`First Course ofFIDM
`Melphalan was administered by 30-minute infusion with a forced
`saline diuresis as previously described.' Eighty-four patients re­
`ceived 140 mg/m^ melphalan. Patients with a glomerular filtration
`rate under 40 mL/min were not included, and patients with a
`glomerular filtration rate between 40 and 50 mL/min received a
`lower dose of HDM (60 to 120 mg/m^). Thus, 12 patients (nine in
`group 1, three in group 2) received lower doses of melphalan (120
`mg/m^ five patients, 100 mg/m^ two patients, 80 mg/m^ four
`patients, 60 mg/m^ one patient) either because of their age,
`physical appearance, or impaired renal function. One patient with
`refractory MM was treated with 100 mg/m^ melphalan on 2
`consecutive days. Eighty-three patients (89%) were treated in
`
`From the Departments of Hematology of Nantes, Paris Saint
`Antoine, Tours, Lille, Lyon, Bobigny, Poitiers, Angers, Rennes, France.
`Submitted June 20, 1991; accepted January 27, 1992.
`Address reprint requests to Jean-Luc Harousseau, MD, Department
`of Hematology, Place Alexis Ricordeau, B.P. 1005, 44035 Nantes
`Cedex 01, France.
`The publication costs of this article were defrayed in part by page
`charge payment. This article must therefore be hereby marked
`“advertisement” in accordance with 18 U.S.C. section 1734solely to
`indicate this fact.
`© 1992 by I'he American Society of Hematology.
`0006-4971192l7911-0009$3.00l0
`
`2827
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`2828
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`HAROUSSEAU ET AL
`
`Table 1. Clinical Characteristics of the Patients
`
`No. of patients
`Sex
`Age (median)
`Type of myeloma* (IgG/lgA/BJ)
`k/X
`Initial OS stage
`Initial p2 microglobulin mg/L (median)
`No. of previous protocols
`No. of previous chemotherapy cycles (median)
`Prior radiotherapy (%)
`No. of patients pretreated with anthracyclines (%j
`Interval diagnosis-HDM (median in mo)
`Interval first treatment-HDM (median in mo)
`Abbreviation: DS, Durie-Salmon.
`*Two nonsecreting MM.
`
`Ail
`97
`57/40
`26-67 (51)
`48/23/24
`65/30
`2/8/87
`1.5-25 (3.3)
`1-5
`0-65 (4)
`19(19.5)
`52 (53.5)
`0-96 (5.5)
`0-91 (4.6)
`
`Group 1
`Advanced MM
`44
`20/24
`29-67 (51)
`21/9/12
`32/10
`1/6/37
`1.7-25 (3.9)
`1-5
`3-65 (14)
`12(27)
`35 (79.6)
`2-45 (23)
`0-91 (19)
`
`Group 2
`Newly Diagnosed MM
`53
`37/16
`26-67 (61)
`27/14/12
`33/20
`1/2/50
`1.5-16(3.3)
`0-2
`0-9 (2)
`7(13)
`17(32)
`0-43 (2)
`0-10(2)
`
`laminar airflow rooms with total gut decontamination. Antibiotics
`and transfusions were used as indicated in each center. Patients
`were categorized according to the M component, the Durie-
`Salmon staging,’' and the p2 microglobulin level (only in 49
`patients, 16 in group 1,33 in group 2).
`Response to HDM was assessed following the criteria defined by
`Gore et al.** Patients were regarded as having achieved CR when no
`paraprotein was measurable by serum proteins electrophoresis,
`when no Bence Jones jrroteinuria was detectable on urine electro­
`phoresis, and when bone marrow aspiration showed less than 5%
`plasma cells. In the majority of cases the absence of paraprotein
`was confirmed by immunofixation. Patients were in partial remis­
`sion (PR) if there was a 50% decrease in M component or bone
`marrow infiltration. All other results were regarded as failures.
`Marrow Collection and BMT
`In the first part of the study (before 1987), marrow was collected
`and cryopreserved only in patients achieving CR after HDM. After
`the publication by Barlogie et aP showing the feasibility of ABMT
`with marrow contaminated with up to 30% of plasma cells, marrow
`was also collected in patients achieving PR. Marrow was not
`purged in vitro, In four cases, peripheral blood stem cells were
`collected instead of marrow.
`The preparative regimen to autologous transplantation was a
`second course of 140 mg/m^HDM alone in the first 18 patients. As
`the tolerance of this procedure was good, the following 17 patients
`received a myeloablative conditioning regimen with high-dose
`chemotherapy (140 mg/m^ melphalan or 120 mg/k cyclophospha­
`mide) plus TBI (16 patients) or the Baltimore regimen busulfan-
`cyclophosphamide’ (one patient previously treated by radiation).
`TBI was administered at a dose of 12 Gy in six fractions in 12 cases
`and 10 Gy single dose in four cases.
`Statistical Analysis
`Actuarial curves were plotted from the date of the first course of
`HDM following the Kaplan-Meier method.’" Differences between
`the curves were analyzed with the log-rank test.” Overall survival
`was defined as the time from first HDM to death. Progression-free
`survival (PFS) was evaluated from the time of remission achieve­
`ment (CR or PR) after the first course of HDM until relapse.
`Relapse was assessed according to criteria defined by Mandelli et
`al’^: 25% increase in the serum paraprotein, increase in the urinary
`paraprotein level to more than 2 g per day, reappearance of the
`paraprotein in serum or urine (for complete responders), increase
`in the size or number of lytic bone lesions.
`
`The following parameters were analyzed for their impact on the
`clinical outcome (CR and overall response rates, survival and
`PFS): sex, age at the date of HDM, heavy- and light-chain isotype,
`initial p2 microglobulin level (< 3 mg/L or > 3 mg/L), response to
`conventional chemotherapy in group 1 (sensitive and untested
`relapses versus primary resistances and resistant relapses), interval
`between the diagnosis or the start of conventional treatment and
`the date of HDM (< 5 and 12 months, > 5 and 12 months), number
`of conventional protocols and number of chemotherapy courses
`administered before HDM, and prior radiotherapy. Response
`rates were compared by the chi-squared test, Nonparametric
`values were compared by the Wilcoxon rank-sum test.’" Correla­
`tion studies were based on the Spearman rank correlation coeffi­
`cient.
`
`RESULTS
`Results of the First Course of HDM
`After the first course of HDM, the overall response rate
`was 71% (69 of the 97 patients): 24 patients achieved CR
`(25%), 45 had PR (Table 2). It should be noted that of
`these 45 PR, 24 were very good PR with less than 5%
`plasma cells in the marrow and at least 90% reduction of
`the M component. There were 28 failures, including eight
`(8%) toxic deaths. The results were better in group 2
`(75.5% responses and 28% CR) than in group 1 (66%
`responses and 20.5% CR), but these differences are not
`significant. In group 1, both CR and response rates were
`higher in 19 untested or sensitive relapses than in 25
`resistant MM (37% and 84%, respectively, v 8% and 52%).
`The results were very poor in the group of resistant relapses
`with no CR and only 5 responses out of 11 patients. Among
`the parameters tested for their influence on the response
`rate, age was the only significant one. Patients 50 years old
`or less had an 83% response rate versus 62% for patients
`over 50 years (P = .036). The CR rate was lower in IgG
`than in non-IgG MM (23% v 51%, F = ,008), but heavy
`chain isotype had no influence on the overall response rate
`(67% V 75.5%, F = .42).
`Toxicity of the First Course of HDM
`The median duration of neutropenia (<0.5 x 10"/L)
`was 24.5 days (range 11 to 180 days) and was longer in
`
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`DOUBLE-INTENSIVE THERAPY IN MULTIPLE MYELOMA
`
`Table 2. Clinical Outcome of the 97 Patients Receiving at Least One Cycle of Intensive Therapy
`Results of the First HDM
`No. of
`CR + PR
`Patients
`69 (71)
`29 (66)
`40 (75.5)
`
`97
`44
`53
`
`CR
`24 (25)
`9 (20.5)
`15(28)
`
`Failure
`
`28
`15
`13
`
`2829
`
`Median Survival
`(mo)
`
`P = .009
`
`P= .06
`
`24
`17
`37
`
`18
`
`50 +
`19
`
`17.5
`14
`7
`23.5
`
`Total {%)
`Group 1 (%) (advanced MM)
`Group 2 (%) (newly diagnosed)
`Age (yr|
`£50
`>50
`Type of myeloma
`IgG
`Non-IgG
`Response to previous therapy
`Sensitive or untested relapse
`Resistant
`Resistant relapse
`Primary resistanse
`
`42
`55
`
`48
`49
`
`19
`26
`11
`14
`
`10
`14
`
`' P =
`19
`
`.008
`
`7
`2 j P = .048
`0
`2
`
`= .036
`
`P
`
`= .056
`
`P
`
`34
`
`32
`37
`
`13
`5
`8
`
`7
`21
`
`16
`12
`
`3
`12
`6
`6
`
`group 1 than in group 2 (29.5 days v 23 days, P = .005)
`(Table 3, Fig lA). The median duration of thrombocytope­
`nia was 18.5 days and was also longer in group 1 than in
`group 2 (32 days v 17 days, P = .03) (Fig IB). Eighteen
`patients in group 1 and seven in group 2 experienced very
`prolonged myelosuppression (more than 30 days). One
`patient in group 1 could never have a hematopoietic
`reconstitution and finally died of a fungal infection. As a
`result of this severe hematologic toxicity, 55 patients had at
`least one episode of documented bacteriemia (26 in group
`1, 29 in group 2) and 25 had at least one clinically
`documented infection (11 in group 1, 14 in group 2). The
`median number of platelet transfusions was seven (range 0
`to 52), with no significant difference between the two
`groups. Eight patients died of infectious complications of
`neutropenia (three in group 1, five in group 2). As the
`myelosuppression was significantly more severe in group 1,
`
`Table 3. Toxicity of the First Course of HDM
`
`Group 1
`(advanced MM)
`N-44
`
`Group 2
`(newly diagnosed
`MM)
`N-63
`
`All
`
`the correlation between the duration of neutropenia and
`the pretreatment characteristics was analyzed in this group.
`None of these parameters was significantly correlated to the
`duration of neutropenia.
`Survival
`The median follow-up time for living patients is 32
`months (9 to 68 months). The median survival for the entire
`group of 97 patients is 24 months with a 26% ± 9%
`probability of being alive at 5 years (Fig 2). The correspond­
`ing figures are, respectively, 17 months and 15% ± 11% at 4
`years in group 1, 37 months and 28.5% ± 13% at 5 years in
`group 2. However, the actuarial survival curves are not
`
`J
`
`P 10-
`a
`9-
`o
`
`0
`
`R
`
`T
`
`7-
`
`5-
`4-
`
`3-
`
`/Tr
`
`r*
`J
`
`f
`
`r"'
`
`Group 1 (44 p^tlants)
`-—— Group 2 (53 patlanta)
`
`p - 0.0005
`
`Dose of HDM mg/m*
`(median)
`No. of patients treated
`with 140 mg/m*
`Duration of neutrope­
`nia (median)
`Duration of thrombo­
`cytopenia (median)
`No. of patients with
`aplasia longer than
`30 d (%)
`No. of patients with
`documented bacte­
`riemia (%)
`No. of patients with
`clinically docu­
`mented infection
`{%)
`No. of toxic deaths
`(%}
`
`60-200(140) 60-200(140)
`
`80-140(140)
`
`80
`
`32
`
`48
`
`11-180(24.5) 12-180(29.5)
`6-240 (32)
`
`1-240(18.5)
`
`11-73 (23)
`
`1-102(17}
`
`25 (26)
`
`55 (57)
`
`25 (26)
`
`8(8)
`
`18(41)
`
`7(13)
`
`26 (59)
`
`29 (55)
`
`11 (25)
`
`3(7)
`
`14(26)
`
`5 (9.5)
`
`1
`I 2-
`1-
`
`0-1
`
`0
`Am
`
`40
`
`,J
`
`. J
`
`f-J
`j
`
`P 10-
`R 9-
`
`0
`p
`0 6-
`
`7-
`
`5-
`
`4-
`
`3-
`
`2-
`
`T
`I
`I
`
`.1.
`
`I
`120
`
`t.
`160
`
`D A
`
`200
`
`.i
`
`GROUP 1 (44 pationta)
`GROUP 2 (53 Fatlenta)
`
`p •> 0.003
`
`0
`
`1-
`
`Bn 0-'
`
`120
`
`.1.
`40
`Fig 1. Duration of neutropenia (A) and of thrombocytopenia (B)
`after the first course of HDM. Comparison between group 1 {advanced
`MM) and group 2 {newly diagnosed MM). Kapfan-Meler plots, log-rank
`test {A), P - .0005; (B), P = .003.
`
`D A Y S
`L
`200
`
`.1,
`160
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`

`2830
`
`P 10-
`R
`9-
`
`O
`
`p
`
`0
`
`R
`
`T
`
`I
`
`I
`
`O
`
`N
`
`7-
`
`6-
`
`S-
`
`4-
`
`3-
`
`iillj
`
`2-
`1 -
`O-
`
`HAROUSSEAU ET AL
`
`p
`
`o
`
`P
`
`O
`
`R
`
`1
`
`O
`N
`
`10-
`9-
`
`7-
`
`6-
`
`5-
`
`4-
`3-
`
`2-
`
`1-
`
`• _ .
`
`1
`
`o-
`
`0
`
`.1
`10
`
`20
`
`30
`
`i.
`40
`
`-L
`50
`Kontha
`Fig 4. Duration of remission in the 69 patients responding to HDM
`-----) and in the 35 patients undergoing autologous transplantation
`
`70 Months
`0
`10
`20
`30
`40
`50
`60
`Fig 2, Overall survival of the 97 patients having received at least
`one course of HDU.
`
`(■
`
`The other 31 patients could not receive a second course of
`high-dose therapy for a variety of reasons (relapse 10, poor
`hematologic recovery or heavy marrow contamination 7,
`poor clinical status 8, severe fungal infection 3, patient’s
`refusal 3). The exclusion rate was higher in group 1 (18 of
`29 responders) than in group 2 (13 of 40 responders).
`Eleven of 44 patients (25%) were transplanted (1 allogenic,
`10 autologous) in group 1 and 27 of 53 (51%) in group 2 (2
`allogenic, 25 autologous). Qf the three allogenic BMTs, one
`was in group 1 and was transplanted in PR after the first
`course of HDM. The other two were in group 2 and both
`were transplanted in PR. All three patients died, one of
`graft-versus-host disease at day 45 post BMT, one from
`interstitial pneumonitis 5 months after BMT, and one from
`bacterial sepsis in apparent CR after 15 months.
`P 10-
`
`9-
`
`8-
`
`7-
`
`0 P
`
`0
`
`6-
`
`R 5-
`
`T
`
`4-
`
`statistically different (P.= .16) (Fig 3). The PFS was evalu­
`ated in the 69 responding (CR + PR) patients (Fig 4).
`Forty-eight of the responders relapsed within 45 months
`and the median duration of response was 20 months with
`no
`significant difference between group 1 (18 months) and
`group 2 (23.5 months).
`In univariate analysis, sex, light-chain isotype, p2 micro­
`globulin level, interval between diagnosis or start of initial
`treatrrient and date of HDM, number of standard dose
`protocols and number of chemotherapy courses adminis­
`tered before HDM, prior radiotherapy had no significant
`impact on the survival and PFS rates. Only the age and the
`response to HDM appear to be of significant value. The
`median survival was 42 months for patients under 50 years
`old and 18 months for patients over this limit, and the
`survival curves differ significantly {P = .009) (Fig 5A). The
`median survival was 28 months for the 69 responders to the
`first course of HDM, and only 7 months for the 28
`nonresponders (P = .02) (Fig 5B). There is a trend in favor
`of a longer survival for patients with IgG MM, but the
`difference does not reach statistical significance by the
`log-rank test (P = .06).
`
`I
`
`3-
`
`I 2-
`
`0
`
`10
`
`20
`
`30
`
`40
`
`50
`
`!
`60
`
`70 Months
`
`0
`A.
`
`1-
`
`0-
`
`0-
`
`9-
`
`R
`
`0
`
`P
`
`7-
`
`O 6-
`
`U
`
`5-
`
`4-
`
`3-
`
`2-
`
`1-
`
`R
`
`I
`
`I 0
`
`Bn O'
`
`i
`70 Months
`Fig 5. Prognostic factors. Influence of the age (A: [—J, age S 50
`years [N == 42}; [—], >50 years [N = 55]) and of the response to the
`first course of HDM (B; [—], responders to HDM [N = 69]; [—],
`nonresponders, to HDM [N - 28]) on the survival. (A), P = .009; (B),
`P = .02.
`
`0
`
`10
`
`20
`
`.1.
`30
`
`,1.
`40
`
`.1,
`60
`
`50
`
`The Second Course of High-Dose Therapy
`Of the 69 responders to HDM, 35 proceeded to autolo­
`gous transplantation (5l% of the responders and 36% of
`the entire group). Three patients less than 45 years old and
`with an HLA-identical sibling underwent allogenic BMT.
`
`P 10-
`
`R
`o
`P
`o
`R
`
`T
`
`I
`
`I
`
`0
`
`N
`
`9-
`
`0-
`
`7-
`
`6-
`
`5-
`
`4-
`
`3-
`
`2-
`
`1-
`
`0-
`
`\
`
`70 Months
`10
`0
`20
`30
`50
`Fig 3. Comparison of the survival curves between advanced MM
`([—1, group 1, N = 44) end newly diagnosed MM ([—], group 2,
`N = 53) (/> = .16).
`
`60
`
`40
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`DOUBLE-INTENSIVE THERAPY IN MULTIPLE MYELOMA
`
`Of the 35 patients undergoing autologous transplanta­
`tions (10 in group 1 and 25 in group 2), 12 were in CR 22 in
`PR and 1 in early relapse at the time of transplant.
`The median interval between HDM and marrow collec­
`tion was 3 months (1.5 to 19 months). In one patient,
`peripheral blood stem cells were collected 2 months before
`the first HDM after one course of conventional chemother­
`apy. The percentage of reinfused plasma cells ranged from
`0 to 30 (median 1). In 22 cases, the marrow contained less
`than S% plasma cells. The median interval between the first
`HDM and autologous transplantation was 5 months (2 to
`23). Only 14 patients were transplanted within 4 months
`after the first HDM. The median duration of neutropenia
`was 24 days and the median duration of thrombocytopenia
`was 49 days (Fig 6). Prolonged thrombocytopenias (longer
`than 90 days) were noted in nine cases. There were two
`toxic deaths (one graft failure with veno-occlusive disease
`in group 1, one aspergillosis in group 2). Of the 22 patients
`in PR, 9 remained in PR, 1 died, 11 converted to CR, and 1
`progressed rapidly after AT. The patient transplanted in
`early relapse went back to CR.
`For the 35 patients undergoing autologous transplanta­
`tion, the median survival is 41 months and the projected
`5-year survival is 28.5% ± 15% (Fig 7). The median
`duration of response is 28 months, but the PFS curve shows
`no plateau, with the last relapse occurring at 45 months (Fig
`5). The clinical outcome after autologous transplantation
`was not influenced by the response after HDM (CR v PR),
`the percentage of plasma cells in the reinfused marrow, the
`use of myeloablative conditioning regimen, or the interval
`between the first HDM and autologous transplantation
`(within or beyond 120 days). The survival and PFS curves
`are not significantly different between the 10 patients in
`group 1 and the 25 patients in group 2.
`
`DISCUSSION
`The objectives of this double-intensive therapy were to
`achieve a high cell mass reduction with the first course of
`HDM and to prolong the remission duration with the
`second course of high-dose therapy. This approach is usual
`in the management of acute myeloid leukemia but had
`never been used in MM. The CR and the response rates
`after the first HDM were 25% and 71%, respectively, which
`is comparable with results obtained previously.^ The only
`
`10-
`9-
`
`7-
`
`6-
`
`5-
`
`4-
`
`3-
`
`2-
`
`, J
`
`.J
`
`ZZJ
`
`J
`
`r
`
`-— PLATELETS > 30x10*/L
`- - NEUTROPHILS > 0,5 xl 0* /L
`
`0-
`
`.1.
`120
`80
`160
`200
`Fig 6. Duration of neutropenia and of thrombocytopenia after
`autologous transplantation.
`
`DAYS
`
`JL
`
`10-
`9-
`
`7-
`
`6-
`
`5-
`
`3-
`
`2-
`
`0
`
`0
`
`I
`
`0
`
`N
`
`2831
`
`1
`
`O-
`
`10
`
`1
`70
`Months
`Fig 7. Survival of the 35 patients undergoing autologous transplan*
`tation.
`
`1
`00
`
`50
`
`parameter influencing the response rate was the age, with
`patients under the age of 50 achieving an 83% response rate
`versus 62% for older ones.
`Despite the good cytoreduction obtained by the first
`course of HDM, the median survival was only 24 months for
`the entire group, 17 months in advanced MM, and 37
`months in newly diagnosed patients. Age under 50 years
`and response to HDM were the only significant prognostic
`factors, while, as already noted after autologous transplan­
`tation, IgG MM appeared to have a slightly better progno­
`sis.In this multicenter study we could not confirm the
`prognostic impact of ^2 microglobulin level. The overall
`response rate and survival did not differ significantly be­
`tween advanced and newly diagnosed MM. As published
`previously,*^ the CR and response rate after HDM were
`satisfactory in primarily resistant MM and sensitive
`or
`untested relapses, but poor in the subgroup of resistant
`relapses. Therefore, this aggressive strategy could be a
`salvage therapy for sensitive relapses or primarily re.sistant
`MM. However, the myelosuppression induced by HDM
`given without any hematopoietic support was severe, lead­
`ing to 8% toxic deaths. The median duration of neutropenia
`was longer in the group of heavily pretreated patients (29.5
`days V 23 days) and it was not possible to correlate the
`duration of neutropenia to any pretreatment characteristic.
`Recombinant hematopoietic growth factors (interleukin-3
`[IL-3], granulocyte-macrophage colony-stimulating factor
`fGM-CSFJ, or G-CSF) could stimulate marrow recovery
`after HDM.*'’-'^ In a preliminary study with GM-CSF, the
`duration of neutropenia was reduced in patients with
`adequate marrow reserve.**’ However, it has been shown
`that these growth factors can stimulate the in vitro prolifer­
`ation of myeloma cells in synergy with IL-fi.*®’*^ Thus, the
`i.ssues of safety and efficacy of GM-CSF after HDM are
`being addressed in an ongoing randomized study versus
`placebo.
`Even if historical comparisons are not recommended, our
`results do not appear to be superior to those achieved with
`only one course of intensive therapy.^'®-*^'^** This could be
`partially explained by the fact that only 25% of patients
`with advanced MM and only 51% of patients with newly
`diagnosed MM had undergone the second course, mainly
`because of the toxicity of the first. However, the main cause
`of failure was relapse because the PFS curve of the 69
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`2832
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`responders shows no plateau. Even in the 35 patients who
`could proceed to the planned autologous transplant, re­
`lapses occurred and their median remission duration was 28
`months.
`Autologous hematopoietic stem cell transplantation has
`been recently introduced in the management of
`In the first pilot studies, this procedure was proposed to
`advanced or refractory
`We were the first to intro­
`duce ABMT as a consolidation therapy for two patients in
`first remission.^ It has been suggested that performing
`ABMT early in the course of the disease could yield a
`higher response rate and reduce the relapse rate.^''* How­
`ever, in the report by Gore et al** on 50 previously untreated
`patients, relapses occurred within the observation period,
`and the 2-year probability of PFS was only 60%. Further­
`more, Jagannath et al*^ have recently shown that results
`comparable with those achieved in first remission can be
`obtained in second remission or even in primarily refractory
`patients. In the present study there was no significant
`difference between previously treated patients and newly
`diagnosed patients in the outcome after autologous trans­
`plantation. Thus, the exact place of ABMT remains to be
`defined by further studies.
`Another way to reduce the relapse rate after ABMT is to
`increase the conditioning regimen. Barlogie et aB have
`suggested that a myeloablative regimen combining TBI and
`high-dose chemotherapy could be superior to chemother­
`apy alone. We could not confirm this statement because
`there was no significant difference in the outcome of the 17
`patients transplanted after myeloablative regimen and of
`the 18 patients transplanted after HDM alone. An alterna­
`tive approach could be the busulfan-cyclophosphamide
`regimen recently proposed by the Seattle group for allo­
`genic transplantation in MM,^' particularly for patients
`with extensive prior radiotherapy.
`The marrow contamination by plasma cells or their
`precursors as a source of relapse remains a critical issue.^^
`Jagannath et al'^ have shown that the extent of plasmacyto-
`sis in autografts did not affect remission or survival times.
`They stated that the presence of up to 30% of terminally
`differentiated tumor cells could be without any prognostic
`relevance if the tumor stem cell compartment is much more
`undifferentiated.^^ However, attempts have been recently
`made to purge the marrow either with cytotoxic agents^'* or
`with monoclonal antibodies.^’^'’ The preliminary clinical
`data show that marrow purging is not harmful and that
`hematopoietic reconstitution is not inhibited. However, the
`phenotype of the clonogenic myeloma cell is undefined and
`the value of depleting marrow with anti-B-cell or anti-
`
`HAROUSSEAU ET AL
`
`plasma-cell antibodies is unclear. The impact of these
`purging techniques on the clinical outcome cannot be
`presently assessed, but early relapses have been ob-
`served.^^'^**
`The use of peripheral blood stem cells is another attrac­
`tive approach because there are fewer myeloma cells in the
`blood than in the bone marrow. This apparent advantage
`has to be demonstrated by clinical trials because of the
`presence of early myeloma progenitors in the peripheral
`blood.27 Preliminary results with peripheral blood stem
`cells are encouraging, but the follow-up is still short.^'^' We
`have chosen another strategy and have hoped that the first
`course of HDM could be an in vivo purging of the marrow
`before collection. This approach was apparently successful
`in 22 patients whose collected marrow contained less than
`5% plasma cells. However, the marrow contamination had
`no significant impact on the outcome. Moreover, marrow
`could not be collected in seven cases because of heavy
`plasma cell infiltration or poor hematopoietic quality.
`Finally hematopoietic recovery after autologous transplan­
`tation was delayed in nine cases. Thus, the feasibility of
`autologous transplantation after a first course of high-dose
`chemotherapy raises several issues that have already been
`underlined in the context of acute myeloid leukemia.^^ As
`proposed by others,**’’^ collection of hematopoietic stem
`cells after standard dose cytoreduction could allow the
`evaluation of autologous transplantation in a larger cohort
`of patients.
`The most important point is that probably none of the
`patients who could tolerate the two intensive courses would
`be cured because the PFS curve shows no plateau. Other
`approaches are needed to improve the results of autologous
`transplantation. One could be the use of a-interferon either
`after the first course of intensive therapy to avoid the
`hazards of the second course or after autologous transplan­
`tation. It has been shown that a-interferon prolongs re­
`sponse and survival in patients with MM responding to
`conventional induction chemotherapy.It is conceivable
`that this beneficial effect could also be obtained in patients
`with minimal residual disease after ABMT. Preliminary
`results with this maintenance therapy are encouraging.^^'^'*
`Thus, high-dose therapy is a new attractive approach in
`the management of MM. Patients responding to HDM may
`have prolonged survival after a second course with autolo­
`gous hematopoietic support. However, even repeated appli­
`cations or myeloablative doses probably cannot eradicate
`the malignant clone. Further studies are warranted to
`better delineate its indications and compare its results to
`those achieved with more conventional strategies.
`
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